Organometallic compounds containing 1, 3, 5-triazine rings



Patented Apr. 12, 1949 UNITED STATES PATENTOFFICE ORGAN OMETALLIC COMPOUNDS CONTAIN ING 1,3,5-TRIAZINE RINGS Ernst A. H. Friedheim, New York, N. Y. No Drawing. Original application May 19,1944,

Serial No. 536,425. Divided and this application June 23, 1945, Serial No. 601,331

said formula representing new compounds consisting of a 1,3,5-triazine ring, at least one carbon atom of which is linked by a NH- group to a phenyl-radical carrying a trivalent antimonyradical or to a substituted phenyl-radical carrying a trivalent antimony radical. D represents a divalent radical selected from the group consisting of O, S, dihalides, radicals of the formula N Q x =Sb L \N/ and sulfur-containing groups of the type =(SR) 2, wherein SR is the residue of a sulfhydril compound of the type HS--R-, and R is selected from the group consisting of aliphatic and cyclic radicals. Such sulfur-containing compounds are, for example thioglycolic acid, cysteine, gluthatione, thiophenol, thioacetic acid, thiobenzoic acid, thioacetamide, thiosalicylic acid, p-sulfhydril-benzene sulfonic acid, thiopropionic acid, psulfhydril-phenylacetic acid.

Compounds according to the present invention correspond to the formula N A 1kg Sb=D wherein X and Y may be equal or difierent and may represent halogens or residues of any inorganic or organic, aliphatic or cyclic, isocyclic or heterocyclic, monocyclic or polycyclic molecule containing an active hydrogen atom capable of 12 Claims. (Cl. 260-242) reacting with. a cyanuric halide with the formation of hydrogen halide. For example, X and Y may be selected from the group consisting of Cl, Br, I, F, H, OH, O-alkyl, O-acyl, NH2, NH-alkyl, N-alkylz, NH-acyl, NHNH2, NH-NH-alkyl, N-alkyl-NI-Iz, N-alkyl-NI-I-alkyl, NH-NH-alkyl, N-acyl-NHz, N-acyl-NH-acyl, NH-aryl, NH CH2) nCoNHz, NH(CI-I2) n-NH2,

--NH (CH2) 'n.--N- dialkyl, NI-HCHz) nOH, NH-CH2CHOHCH2OI-I,

--NHOI-I, NHCN NH-C-NH -NHONH-CN ILIH NH residues of cyanamide derivatives, residues of substituted guanidines, amino-derivatives of carbohydrates, particularly amino-derivatives of monosaccharides, such as glucose-amine, SH, substituents of the type SR. wherein R stands for any aliphatic or cyclic group capable of carrying a SH group, such as thioglycolic acid and thiophenol, alkyl radicals and their substitution products, isocyclic and heterocyclic radicals, which may be monocyclic or polycyclic, and their substitution products, such as O-aryl groups, substituted aryl radicals, such as those corresponding to the formula wherein A and B may represent equal or different substituents defined further below, and E may represent a radical being in ortho-, metaor para-position to the --NH- or -NH--NH-group, and selected from the group consisting of 8031-1, SO2NH2, COOH, X and/or Y may also stand for radicals of the formula or for 1,3,5-triazine groups or residues of tria'zine derivatives. These radicalsv and said triazine groups are residues of triazine derivatives standing for X and/or Y may be linked directly or indirectly to the ring carbon atoms of the first or central triazine ring. In the latter case, the link between the substituting X, Y radical and the ring carbon atom of the first or central triazine ring may be formed by a cyclic or aliphatic amine radical for example by an NH-aryl, NH-alkyl, NH-NH-aryl or NH-NH-alkyl radical. The link between the first or central triazine ring standing for X and/or Y may be formed by an NH-, NH-NH group or an aliphatic or cyclic diamine, for example of the formula NHCeH4-NH- or NHCH2CH2NH.

A and B may be the same or different, and are selected from the group consisting of hydrogen,

halogen, --NO2, -OI-I, --alkyl, -amino, substituted amino-, and alkyl radicals. The antimony-containing group may be in ortho-, metaor para-position with respect to the --NH-group.

The compounds embodying the present invention may be prepared by reacting a derivative of 1,3,5-triazine containing at least one active halogen with an aminophenyl compound carrying a radical of trivalent antimony. The compounds according to the invention may also be obtained by reacting a halogen-phenyl compound carrying a radical of trivalent antimony with a triazine derivative containing at least one amino-group with active hydrogen. Furthermore, compounds according to this invention may also be obtained by preparing a triazinyl-amino-phenyl-compound carrying in the amino-phenyl-group a trivalent antimony radical and interchanging one or more active atoms linked to the triazine ring, or to the benzene ring or to the antimony radical with other suitable radicals. Compounds of the general formula l I may be, for example, obtained by refluxing a compound corresponding to the formula Sb=D in a non-oxidizing atmosphere with aqueous alkali solution. Or a compound corresponding to the formula the formula Sb=D Furthermore compounds of the type X t a Na may be obtained by subjecting, for example, a compound corresponding to the formula to the action of asuitable reducing agent such as stannous chloride or hypophosphorus acid (HzPOa) in hydrochloric acid solution in the pres-- ence of HI, or sodium hydrosulfite (NazSzOQ in,

alkaline solution.

Example I.A solution of 16.5 parts by weight of [3-aminophenyl] -stibinous dichloride hydrochloride in 300 parts by weight of water is added dropwise to a fine suspension of 9.22 parts by Upon the addition of dilute ice-cold aqueous ammonium hydroxide, the corresponding 2,4- dlchloro-1,3,5-triazinyl-(6) aminophenyl antimony oxide of the formula N N Cl-JJ (EL-NEG N sibo is formed and may be separated from the liquid as a white precipitate. This compound may be converted into the corresponding 2-chloro-4- amino-1,3,5-triazinyl compound by subjecting it to the further action of ammonia in a non-oxidizing atmosphere. For example, the above mentioned moist white precipitate is covered with times the quantity of 10% ammonia and shaken at 45 C. for about 1 hour, the excess ammonia is removed under reduced pressure and finally the reaction mixture is acidified with acetic acid. The resulting z-chloro-i-amino-1,3,5-triazinyl- (6) -amino-phenyl-antimony oxide is sparingly soluble in aqueous solutions of alkali hydroxides, and in excess dilute hydrochloric acid. By treating the above described 2,4-chloro-1,3,5-triaziny1- (6) -aminophenyl stibinous compounds with aqueous ammonia under pressure, both Cl-atoms of'th triazine ring may be substituted by NH2 groups. Furthermore, one or both of these Clatoms may be interchanged with substituted amino-groups by treating the chloro-triazine derivatives for example with alkylamines, hydroxy-alkyl amines or dialkyl-amino-alkyl amines.

Example II.--I.3 parts by weight of chlorocyanuric-diamide are refluxed with a solution of 11.5 parts by weight of [3-amino phenyllstibinous oxide in 500 parts by weight of 1 aqueous hydrochloric acid in a non-oxidizing atmosphere until the reaction of primary amine has become negative in the solution. After this period of heating the solution is allowed to cool in an ice bath, and a current of H01 gas is passed to precipitate the reaction product formed. The

amas

precipitate consists substantially of a compound corresponding to the formula N sbounoi By the action of dilute, cold aqueous H4N.0H, this compound may be converted into the corresponding antimony oxide compound.

Example III.--l6.88 parts by weight oi 3- amino-4-hydroxy phenyldichlorostibine hydrochloride of the formula oH-Qsbot-aci are dissolved in 1000 parts by weight of 1% aqueous hydrochloric acid and refluxed with 7.3.parts by weight of chloro-cyanuric-diamide in a nonoxidizlng atmosphere until the reaction of primary amine in the solution has become negative. The solution is then cooled in an ice-bath, and precipitated by a current of HCl gas passed through the solution. The precipitate thus obtained corresponds to the formula met it.

SbChHCl Example I V.A solution of 16.5 parts by weight of l-amino-phenyl dichlorostibine hydrochloride of the formula mN-Qsbotnm mula Example V.A triazine derivative of the for- H 6 mula are added to an aqueous solution of 2.6 g. of potassium thioglycolate. The mixture is moderately heated in a non-oxidizing atmosphere and is adjusted to a pH of about 8.0 with NazCOa. From the solution thus obtained the free acid may be precipitated by acidifying for example by the introduction of S02 gas. 3

By using .an equivalent amount of sodium thiosalicylate, instead of the potassium thioglycolate in the above example, a compound corresponding to the formula- NH; g,

may be obtained in a substantially similar manner.

Example VI.-1.4 g. of p-aminophenyl stibinous chloride are suspended in 45 cc. of methylalcohol. The suspension is mixed with a solution of 1.0 g. of thioglycolic acid in methyl alcohol. The reaction mixture is heated on the steam bath for 1 hour, filtered and allowed to cool. On cooling, a reaction product formed according to the following scheme separates as a precipitate:

The precipitate thus formed is dissolved in .the minimum amount of 12/20 aqueous sodium hydroxide, and the solution is reacted with 1.5 g. of 2,4-diamino-6-chloro-1,3,5-triazine while passing a stream of nitrogen through the reaction mixture until the reaction of primary amine has become negative in the solution. The reaction mixture is then saturated with CO2, charcoaled and filtered. The clear filtrate is precipitated by acidiiying, preferably with S02 gas, the precipitate is filtered ofif, washed with aqueous S02 solution and alcohol, and dried under reduced pressure. The reaction product formed corresponds to the formula This compound is soluble in dilute aqueous sodium bicarbonate, sodium hydroxide, potassium hydroxide, diethylamine. It is insoluble in chloroform and ether. It is precipitated from its alkaline solution on acidifying with acetic or mineral acids, but is redissolved in excess dilute mineral acid. Dissolved in an excess of strong alkali it gives a purple color on addition of sodium nitroprussate. It decolorizes hot Fehling solution and dissolves without color in concentrated sulfuric acid. It has a high therapeutic index amounting up to 20-25 in experimental trypanosomiasis (Trypanosoma equiperdwm) in the mouse. One single well tolerated dose of its water-soluble alkali-salts causes rabbits the spirochetes to disappear in syphilitic chancres within 24 hours.

Example VII.--2.8 g. of a condensation product corresponding to the formula CODE 01 Ha! sb G \s l and obtained by reacting one mol of p-aminophenyl stibinous chloride with 2 mols of thiosalicyclic acid are reacted with chlorocyanuric diamide substantially in the manner described in Example VI. The reaction product thus formed corresponds to the formula J -Ox COOH COOH

The product thus formed is soluble in dilute aqueous solutions of NaHCOa and NazCOa.

Analogous products in which the trivalent Sbatom carries SR radicals consisting of the residues of thioglycolamide, thiopropionic acid, 8-mercapto-quinoline, 2-mercapto-pyridine, cysteine or gluthatione may also be prepared according to the above described methods.

Example IX.-3.5 g. of 4-chloro-3-aminophenyl stibinous chloride hydrochloride are dissolved in 200 g. of 1% aqueous hydrochloride acid and refluxed with 1.5 g. chlorocyanuric diamide in a non-oxidizing atmosphere until the reaction of primary amine has become negative in the solution. The solution is then cooled in an ice bath, 0 and then precipitated by the introduction of HCl gas. The precipitate corresponds to the formula SbClaHCl Reference is made to my co-pending patent application Serial No. 536,425 filed on May 19, 1944, now patent 2,430,461, Nov. 11, 1947, of which this is a division.

It is to be understood that in the present specification and claims the term amino-radical is used to include -NI-I2 as well as the above disclosed substituted amino radicals.

I claim:

1. A new 1,3,5-triazine compound consisting of a 1,3,5-triazine ring, one ring carbon atom of which is linked to an aminophenyl group substituted in the benzene ring by a radical of the formula Sb=(SR) 2, while the other ring carbon atoms of said triazine ring are linked to a substituent selected from the group consisting of halogens, OH and amino radicals, the radical SR. being selected from the group consisting of allphatic, aromatic, pyridineand quinoline-sulfhydril radicals.

2. A new 1,3,5-triazine compound of the formula wherein A and B are selected from the group consisting of H, halogen, amino, and OH N -d -NIL-O-sbo ZHSQ-SOIH ------i fi- -Q t-Q sb= sR A B wherein A and B are selected from the group consisting of H, halogen, amino, and OH radicals, and SR is selected from the group consisting of aliphatic, aromatic, pyridineand quinoline-sulfhydril radicals.

4. A new 1,3,5-trlazine compound of the formula wherein A and B are selected from the group consisting of H, halogen, amino, and OH radicals, and --SR is selected from the group consisting of aliphatic, aromatic, pyridineand quinoline-sulfhydril radicals.

5. A new 1,3,5-triazine compound of the formula JNH l Sb(S-CH COOH) N l 1% wherein A and B are selected from the group consisting of H, halogen, amino, and OH radicals.

6. A new 1,3,5-triazine compound of the formula wherein A and B are selected from the group consisting of H, halogen, amino, and -OH radicals.

7. In a process for preparing a 1,3,5-triazine compound as claimed in claim 1, the step comprising reacting a 1,3,5-triazine derivative substituted at one ring carbon atom by a Z-substituent selected from the group consisting of halogen and amino-radicals, while the other ring carbon atoms of said triazine ring are linked to a substituent selected from the group consisting of halogen, OH and amino radicals, witha substituted phenyl antimony compound of the formula Sb=(SR)z A B wherein A and B are selected from the group consisting of H, halogen, amino and OH radicals, and one of Z and W is a halogen radical and the other is an amino radical, and the radical SR is selected from the group consisting of aliphatic, aromatic, pyridineand quinoline-sulfhydril radicals.

8. In a process for the preparation of a 1,3,5- triazine derivative of the formula wherein A and B are selected from the group consisting of H, halogen, amino and --OH radicals, and -SR. is selected from the group consisting of aliphatic, aromatic, pyridineand quinolinesulfhydril radicals, the step comprising reacting cyanuric chloride with an aminophenyl-antimony compound of the formula 9. In a process for the preparation of a 1,3,5- triazine derivative of the formula wherein A and B are selected from the group consisting of H, halogen, amino and -OH radicals, and SR is selected from the group consisting of aliphatic, aromatic, pyridineand quinoline-sulfhydril radicals, the step comprising reacting chloro-cyanuric diamide with an aminophenyl-antimony compound of the formula zN- I I I Sb SR) A B 2 10. In a process for the preparation of a 1,3,5- triazine derivative of the formula wherein A and B are selected from the group consisting of H, halogen, amino and -OH radicals, and SR is selected from the group consisting of aliphatic, aromatic, pyridineand quinoline-sulfhydril radicals, the step comprising reacting cyanuric chloride with an aminophenyl-antimony compound of the formula to form a dichloro-triazinyl-aminophenyl-antimony compound, and subjecting the latter to the action of ammonia.

11. In a process for preparing a 1,'3,5-triazine compound as claimed in claim 1, the step of reacting one mol of a compound of the general formula wherein X, Y may be equal or different and stand for a radical selected from the group consisting of halogens, OH and amino radicals, A and B are selected from the group consisting of H, halogen, amino and -OH radicals, and D stands for a radical selected from the group consisting of dihalogens and O, with at least two mols of a compound of the formula HSR, wherein the radical SR is selected from the group consisting of aliphatic, aromatic, pyridineand quinolinesulfhydril radicals.

12. A process as claimed in claim 11, in which -SR stands for the residue of a thioacid salt.

ERNST A. H. FRIEDHEIM.

No references cited. 

